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This comparative magnetic resonance imaging (MRI) analysis evaluated the ratio of AC-PC (anterior commissure to posterior commissure) distance measures in selected groups of humans and nonhuman primates (NHPs). An understanding of the basis of this ratio between primate species may allow more accurate translation of NHP stereotactic targeting measurements to upcoming human trials. MRI datasets of adult humans [n=21], and juvenile and adult NHPs (Macaca fascicularis [n=40], and Macaca mulatta [n=32]), were evaluated in a mid-sagittal plane to obtain the AC-PC distance measure for each examined subject. Two trained evaluators, blinded to each other's results, carried out three separate measurements of the AC-PC length for each subject. Each observer carried out measurements of the entire dataset [n=93] before repeating the measurements two additional times. Previous dataset measures were not available for review at the time of subsequent measures. Inter- and intra-observer variabilities were not statistically significant. Minimal intraspecies variation was found in the AC-PC measurement of our human and NHP groups. We found significant interspecies differences, however, more between humans and NHPs, and less between the NHP groups. Regression analysis confirms the strong linear relationship of AC-PC distance based primarily on species in our study groups. Human/NHP AC-PC ratios varied between 2.1 and 2.3 based on the compared NHP species groups. We conclude that the scale differences in brain measurements between NHPs and humans described in this study allows improved translation of stereotactic targeting coordinates in future human clinical trials, which may lead to improved efficacy and safety.

Two types of sinenxan A derivatives with different side chains at C-5 were synthesized and evaluated for their in vitro multidrug resistant reversal activities. Several derivatives exhibited better activities than the positive control verapamil. The structure-activity relationships of these derivatives suggested that a carbonyl group at C-13 and the length of side chain at C-5 are important for the activity.

Four new minor taxanes (1-4) have been isolated from Ts-19 cell cultures of Taxus chinensis together with five known taxanes (5-9) by silica gel chromatography combined with semi-preparative HPLC chromatography. On the basis of the analyses of the chemical and spectroscopic (IR, MS, 1D, and 2D NMR) data, the structures of new compounds were elucidated as 5alpha-hydroxy-2alpha,10beta-diacetoxy-14beta-(3-hydroxy-2-methyl-butyryl)oxytaxa-4(20),11-diene (1), 2alpha,5alpha,10beta-triacetoxy-14beta-(2-hydroxy-propionyl)oxytaxa-4(20),11-diene (2), 2alpha,5alpha,10beta-triacetoxy-14beta-(2-hydroxy-3-methyl-butyryl)oxytaxa-4(20),11-diene (3), and 2alpha-benzoxy-4alpha,9alpha,10beta,13alpha-tetraacetoxytax-11-ene (4), respectively. Compounds 1-5 were pharmacologically evaluated for their cytotoxicities against five human cancer cell lines (HCT-8, Bel-7402, BGC-823, A549, and A2780) and their reversing activity towards multi-drug resistance A549/taxol tumor cell line, and the results showed that all of the tested compounds exhibited very low cytotoxicities, while compound 4 possessed twice the reversing activity as that of verapamil at 10 muM.

The stereotactic delivery of therapeutic agents into brain has been problematic because of reflux and leakage of the delivered agent. Good distribution of infusates by convection-enhanced delivery (CED) depends very much on cannula design, precise cannula placement and infusion rates. We have recently published cannula targeting data for the non-human primate (NHP) putamen in which we defined infusion parameters referred to as "red", "blue", and "green" zones for cannula placements that result in poor, sub-optimal and optimal volumes of distribution (Vd), respectively. Therefore, we applied our observations in NHP putamen to the rat brain. Initially, trypan blue dye was infused into agarose gels to evaluate distribution and reflux characteristics of a scaled-down cannula without step and 1-mm stepped cannula. "Stepped" means a sharp transition from a wider stent to a narrower tip; thus the distance of the cannula tip to the larger diameter attachment defines the step distance. Reflux was contained with the stepped design even with an infusion rate of 3.0 microl/min and large infusion volumes in the agarose gel study. Infusions of a recombinant growth factor, GDNF, into rat striatum demonstrated that the presence of a 1-mm stepped cannula prevented reflux and resulted in excellent distribution of GDNF in the striatum. We conclude that a stepped cannula with a 1-mm tip is important for achieving reliable distribution of infused agents in rat brain. It should be considered when local therapies such as gene transfer, local protein administration or cellular replacement are evaluated in rodent models.

Direct delivery of therapeutic agents to the human central nervous system remains an inadequately studied field. Our group has extensively studied and refined a powerful method for distributing various macromolecules and nanoparticles into the parenchyma by means of a procedure called convection-enhanced delivery (CED). First, we developed an improved design of infusion cannula that greatly decreased the likelihood of reflux of infusate up the outside of the cannula. Second, we began to use liposomes loaded with the MRI contrast reagent, Gadoteridol (Gd), to track infusions into brain parenchyma in real time. This innovation generated a wealth of quantitative and qualitative data that in turn drove further improvements in CED. In this chapter, we review many of the recently devised methods needed to ensure controlled distribution of therapeutic agents in the brain.

A methodology was developed for the efficient synthesis of 2,3-unsubstituted nitro containing indoles via acid catalyzed intramolecular electrophilic cyclization. Subsequent reduction of nitro groups allows the construction of some indole fused heterocycles and indole quinone diimines. This strategy provides an efficient method for the preparation of biologically and medicinally interesting molecules.

Direct delivery of therapeutic agents to the human central nervous system remains an inadequately studied field. Our group has extensively studied and refined a powerful method for distributing various macromolecules and nanoparticles into the parenchyma by means of a procedure called convection-enhanced delivery (CED). First, we developed an improved design of infusion cannula that greatly decreased the likelihood of reflux of infusate up the outside of the cannula. Second, we began to use liposomes loaded with the MRI contrast reagent, Gadoteridol (Gd), to track infusions into brain parenchyma in real time. This innovation generated a wealth of quantitative and qualitative data that in turn drove further improvements in CED. In this chapter, we review many of the recently devised methods needed to ensure controlled distribution of therapeutic agents in the brain.

Convection-enhanced delivery (CED) has recently entered the clinic and represents a promising new delivery option for targeted gene therapy in Parkinson’s disease (PD). The prime stereotactic target for the majority of recent gene therapy clinical trials has been the human putamen. The stereotactic delivery of therapeutic agents into putamen (or other subcortical structures) via CED remains problematic due to the difficulty in knowing what volume of therapeutic agent to deliver. Preclinical studies in non-human primates (NHP) offer a way to model treatment strategies prior to clinical trials. Understanding more accurately the volumetric differences in striatum, especially putamen, between NHP and humans is essential in predicting convective volume parameters in human clinical trials. In this study, magnetic resonance images (MRI) were obtained for volumetric measurements of striatum (putamen and caudate nucleus) and whole brain from 11 PD patients, 13 aged healthy human subjects, as well as 8 parkinsonian and 30 normal NHP. The human brain is 13–18 times larger than the monkey brain. However, this ratio is significantly smaller for striatum (5.7–6.5), caudate nucleus (4.6–6.6) and putamen (4.4–6.6). Size and species of the monkeys used for this comparative study are responsible for differences in ratios for each structure between monkeys and humans. This volumetric ratio may have important implications in the design of clinical therapies for PD and Huntington’s disease and should be considered when local therapies such as gene transfer, local protein administration or cellular replacement are translated based on non-human primate research.

Purpose: The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability. We investigated the effects of NO donors, l-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats. Experimental Design: The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and l-arginine. BTB permeability, defined by the unidirectional transport constant, Ki, for [14C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, l-citrulline, and cGMP in the tumor and normal brain tissue were measured. Results: Oral administration of l-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (KCa) channel that is a cGMP pathway effector. The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, l-citrulline, a byproduct of NO formation from l-arginine, and cGMP were enhanced in the tumor tissue by oral administration of l-arginine and/or hydroxyurea. Conclusions: Oral administration of l-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.

The blood-brain tumor barrier (BTB) significantly limits delivery of effective concentrations of chemotherapeutic drugs to brain tumors. Previous studies suggest that BTB permeability may be modulated via alteration in the activity of potassium channels. In this study, we studied the relationship of BTB permeability increase mediated by potassium channel agonists to channel expression in two rat brain tumor models. Intravenous infusion of KCO912 (K(ATP) agonist), minoxidil sulfate (K(ATP) agonist) or NS1619 (K(Ca) agonist) increased tumor permeability more in the 9L allogeneic brain tumor model than in the syngeneic brain tumor model. Consistently, expression of both K(ATP) and K(Ca) channels in 9L tumors was increased to a significantly greater extent in Wistar rats (allogeneic) as compared to Fischer rats (syngeneic). Furthermore, as a preliminary effort to understand clinical implication of potassium channels in brain tumor treatment, we determined the expression of K(ATP) in surgical specimens. K(ATP) mRNA was detected in glioblastoma multiforme (GBM) from nineteen patients examined, with a wide range of expression levels. Interestingly, in paired GBM tissues from seven patients before and after vaccination therapy, increased levels of K(ATP) were detected in five patients after vaccination that had positive response to chemotherapy after vaccination. The present study indicates that the effects of potassium channel agonists on BTB permeability are different between syngeneic and allogeneic models which have different expression levels of potassium channels. The expression of potassium channels in brain tumors is variable, which may be associated with different tumor permeability to therapeutic agents among patients.

The blood-brain tumor barrier (BTB) significantly limits delivery of therapeutic concentrations of chemotherapy to brain tumors. A novel approach to selectively increase drug delivery is pharmacologic modulation of signaling molecules that regulate BTB permeability, such as those in cGMP signaling. Here we show that oral administration of sildenafil (Viagra) and vardenafil (Levitra), inhibitors of cGMP-specific PDE5, selectively increased tumor capillary permeability in 9L gliosarcoma-bearing rats with no significant increase in normal brain capillaries. Tumor-bearing rats treated with the chemotherapy agent, adriamycin, in combination with vardenafil survived significantly longer than rats treated with adriamycin alone. The selective increase in tumor capillary permeability appears to be mediated by a selective increase in tumor cGMP levels and increased vesicular transport through tumor capillaries, and could be attenuated by iberiotoxin, a selective inhibitor for calcium-dependent potassium (K(Ca)) channels, that are effectors in cGMP signaling. The effect by sildenafil could be further increased by simultaneously using another BTB "opener", bradykinin. Collectively, this data demonstrates that oral administration of PDE5 inhibitors selectively increases BTB permeability and enhances anti-tumor efficacy for a chemotherapeutic agent. These findings have significant implications for improving delivery of anti-tumor agents to brain tumors.

A series of C2-modified 10-deacetyl-7-propionyl cephalomannine derivatives was designed, prepared, and biologically evaluated. Some C2 meta-substituted benzoate analogues showed potent activity against both drug-sensitive and drug-resistant tumor cells in which resistance is mediated through either P-gp overexpression or b-tubulin mutation mechanisms. The taxoid 15b and related compounds are of particular interest, as they are much more cytotoxic than paclitaxel, especially against drug-resistant tumor cells; they are able to kill both drug-resistant and drug-sensitive cells (low R/S ratio), and they have high affinity for β-tubulin. Our research results led to an important hypothesis, that is, a taxane with very high binding affinity for β-tubulin is able to counteract drug resistance, which may assist in future taxane-based drug-discovery efforts., The authors thank the Foundation for the Author of National Excellent Doctoral Dissertation of P. R. China (Grant No. 199949), the Fok Ying Tong Education Foundation (Grant No. 91037), and the National Natural Science Foundation (Grant No. 20572135) (to W.-S.F.); the Dirección General de Investigación Científica y Tecnológica (DGICYT, Grant BFU2004-00358), the Comunidad Autonoma de Madrid (Grants CAM200520M061 and BIPPED-CM), the Ministerio de Educación y Ciencia of Spain (Grant BFU-2004-0038) (to J.F.D.); and the Canadian Cancer Society (to F.J.S.) for financial support.

In a variety of tumors, the susceptibility of the tumor cells to apoptotic cell death following chemotherapy is a major determinant of therapeutic outcome. Gliomas are resistant to most chemotherapeutic agents, and its mechanism is not known in detail. In an attempt to understand the mechanism of chemo-resistance, we investigated the roles of insulin-like growth factor-I (IGF-I), IGF-I receptors (IGF-IR), and their relationship with the apoptotic response of two glioma cell lines to etoposide, a chemotherapeutic agent for malignant gliomas.Two human glioma cell lines, U-87MG and KNS-42, were used. Etoposide-induced cell growth inhibition was quantified using a modified MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide), colorimetric assay. Hoechst 33258 staining, DNA fragmentation assay, and western blot were used for the evaluation of apoptosis. ApoAlert caspase assay was used for measuring the activity of caspase-3 (CPP32) and interleukin-1 beta -converting enzyme (ICE) protease. In addition, the effect of IGF-IR antisense was tested in U-87MG and KNS-42 glioma cell lines.Etoposide inhibited the growth of U-87MG and KNS-42 cells in a concentration-dependent manner. Etoposide increased the expression of wild-type p53, activated CPP32 (but not ICE) activity, and induced apoptosis in these cells. IGF-I prevented etoposide-induced apoptosis by increasing the expression of bcl-2 and decreasing the activity of CPP32. IGF-IR antisense enhanced the apoptotic effect of etoposide.IGF-I decreased etoposide-induced apoptosis in glioma cells by increasing the expression of bcl-2 and decreasing the activity of CPP32. The antisense of IGF-IR increased etoposide-induced apoptosis. The anti-apoptotic effect of IGF-I and IGF-IR might be related to the chemo-resistance of glioma to chemotherapeutic agents.

Extraction of craniofacial anatomical structures on cephalometric radiographs is important for observing and predicting the growth changes and evaluating the curative effect in orthodontic analysis. Due to the natural of cephalograms, it is difficult for simplex image processing approaches to exactly track both the soft tissue contours and the structure outlines of internal skull. In this paper, we address this problem by recognizing 262 landmark points and then connecting them according to the prior knowledge. Image processing, pattern matching, and modified active shape model are combined to realize the landmark recognition; subdivision curves are used to obtain the structure rendering.

With the objective of tracing out all craniofacial structures in parallel with landmarking on X-ray images in cephalometry for the first time, a novel approach is proposed to locate 262 feature points composed of 90 landmarks and 172 auxiliary points. Twelve landmarks are identified by classical image processing techniques and a pattern matching algorithm, and then are used to divide the craniofacial shape to ten independent regions according to the anatomical knowledge. For each region, principal component analysis is employed to statistically characterize its shape and the gray profile of every feature point in the training, and a modified active shape model is proposed for localization. We conclude with experiment results and some discussion.

1(3H)‐Isobenzofuranone (phthalides) and its derivatives possess a wide range of biological activities. A new method was found for the synthesis of 3‐substituted phthalides featured with the convenient condensation reaction of 3‐ethoxyphthalide with carbanions in high yields.

Bromocriptine, a dopamine agonist, is now an accepted primary therapeutic agent for patients with prolactinomas and other pituitary adenomas. In this study, we demonstrated that bromocriptine inhibited the proliferation of murine ACTH-secreting pituitary adenoma (AtT-20) cells. In addition, the antitumor activity of bromocriptine was inhibited both by actinomycin D and cycloheximide, suggesting that it was dependent on new RNA and protein synthesis. Interestingly, the results of DNA fragmentation assays and cell cycle analysis clearly demonstrated that bromocriptine induced apoptosis in AtT-20 cells.

Until recently, surgery for pineal region tumours has met with poor results. Although experience remains limited, developments in imaging, surgical approaches, and microsurgery have improved outcomes. Over 26 years we treated 36 patients including: 24 with germinoma; four, teratoma; three, pineal cyst; and one each, embryonal carcinoma, choriocarcinoma, pineocytoma, pineoblastoma and metastasis. All 24 germinomas responded to radiotherapy, as did one case each for teratoma, pineoblastoma, and choriocarcinoma. Eight patients underwent resection, and one patient with germinoma had biopsy via endoscopy. Occipital transtentorial and parieto-occipital transcallosal approaches were used in three each, and infratentorial supracerebellar and a combined infratentorial supracerebellar and occipital transtentorial approach in one each. Total removal was achieved in four patients (50%), and subtotal removal in two. Postoperative complications resolved within 2 weeks. Two patients had recurrence and one had dissemination. All tumours except germinomas should be explored and diagnosed histologically. Current operative techniques allow safe, effective removal of pineal region tumours.

The overexpression of the multidrug resistance (mdr1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumors. Recent studies demonstrate that SN-38, a metabolite of the camptothecin (CPT) derivative CPT-11, has antitumor effects on several tumors, but the mechanisms responsible for its cytotoxicity remain unclear. We therefore determined whether SN-38 has cytotoxic effects on MDR human glioblastoma GB-1 cells and non-MDR human glioblastoma U87-MG cells. Furthermore, we determined what role SN-38 plays in the induction of cytotoxicity in these tumor cells. In this study, we demonstrated that SN-38 had significantly stronger antitumor effects on GB-1 and U-87MG cells than did CPT (P < 0.01 and P < 0.05, respectively). In addition, findings obtained using a DNA fragmentation assay, Hoechst 33258 staining, in situ end-labeling and cell cycle analysis demonstrated that SN-38 induced apoptosis in these tumors. Our results suggest that SN-38 has a stronger antitumor effect on malignant glioma cells regardless of MDR expression than does CPT, and therefore can be considered a new chemotherapeutic agent potentially effective in the treatment of human primary or recurrent malignant gliomas resistant to chemotherapy.

An efficient, one-pot synthesis of 4-methylisoquinolines via a cascade Pd-catalyzed Heck reaction, intramolecular cyclization and isomerization has been developed. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields.

Spingosine-1-phosphate receptor 1 (S1P1) has been actively pursued as an important therapeutic target in immune regulation. A series of 2-substituted 2-aminopropane-1,3-diols were designed and synthesized as selective S1P1 agonists. Most of the compounds with a biphenyl ether scaffold showed moderate to excellent S1P1/S1P3 selectivity. Compound 40c is identified as a potent S1P1 agonist with 350-fold S1P1/S1P3 selectivity. 39c, the alcohol form of 40c exerted good lymphopenia activity in vivo but with weak influence on heart rate. To investigate the SARs of 2-substituted 2-aminopropane-1,3-diols in more details, COMFA (q2 = 0.547, r2 = 0.986) and COMSIA (q2 = 0.544, r2 = 0.943) models were established based on molecular docking alignment, which were validated with high reliability in predicting activities of agonists. The 3D-QSAR models will be helpful in the design of novel, potent and selective S1P1 agonists.

✓ The authors found that multidrug-resistant human glioblastoma GB-1 cells demonstrated significantly more resistance to cisplatin than did nondrug-resistant human glioblastoma U87-MG cells (p < 0.1). They therefore attempted to determine whether calcium channel blockers enhance the antitumor activity of cisplatin against GB-1 cells. Nifedipine, a dihydropyridine calcium channel blocker, significantly enhanced the antitumor effect of cisplatin on GB-1 cells (p < 0.05). In the absence of normal extracellular Ca++, nifedipine enhanced the cytotoxicity of cisplatin. In addition, the antitumor activity of combined cisplatin and nifedipine was inhibited both by actinomycin D and cycloheximide, suggesting that such activity is dependent upon new RNA and protein synthesis. Surprisingly, DNA fragmentation assay demonstrated that synergism between cisplatin and nifedipine resulted in apoptosis (programmed cell death) at a relatively low concentration of cisplatin, which when tested alone did not induce apoptosis. In addition, it was demonstrated that nuclei from GB-1 cells lacked a Ca++-dependent endonuclease that degrades chromatin into nucleosomes and that calcium ionophore A 23187 did not decrease the viability of GB-1 cells. The above findings suggest the hypothesis that the noncytotoxic agent nifedipine synergistically enhances the antitumor effect of cisplatin on multidrug-resistant GB-1 cells lacking Ca++-dependent endonuclease, and subsequently induces apoptosis via its interaction with an as yet uncharacterized functional site other than the calcium channel on GB-1 cells.

A number of racemic 1,3-dimethyl-4-phenylpiperidines which serve as intermediates in the synthesis of opioid analgesics have been resolved on two commercially available high-performance liquid chromatography columns containing cellulose-based chiral stationary phases: Chiralcel OD and Chiralcel OJ. The resolution results were complementary between the two columns. Also, the polarity of substituents appears to play an important role on the ability of the Chiralcel OD column to resolve pairs of enantiomers.

11-Hydroxy-3-(1',1'-dimethylheptyl)hexahydrocannabinol (1) was synthesized from the known cannabimimetic analog (+/-)-nabilone. Racemic 1 was resolved by HPLC on a semipreparative CHIRALCEL OD column (Daicel, Inc.), and pharmacological activities of the individual enantiomers were evaluated in the mouse model. The (-)-enantiomer was found to be much more potent than the (+)-enantiomer in all the four measures with the potency ratios in the production of catalepsy (RI), hypoactivity (SA), hypothermia (RT), and antinociception (TF) being 93, 143, 186, and 322, respectively. The racemic 11 alpha-OH diastereomer (2), a reaction side product, was also evaluated in the mouse model. Only small differences in the pharmacological activity of racemic 1 and 2 were found in the above four measures.

We studied the effect that treating two types of glioblastoma cell lines, U-87 MG and U-251 MG, with interferon (IFN)-gamma had on their susceptibility to lysis by lymphokine-activated killer (LAK) cells. We also examined the participation of cell-adhesion molecules and major histocompatibility complex (MHC) class I and II antigens present on the target cells in lysis by LAK cells. Treatment with IFN-gamma (1000 U/ml) for 48 hours resulted in the increased expression of both intercellular-adhesion molecule 1 and MHC class I antigens on tumor cells. In addition, untreated tumor cells expressed neural-cell-adhesion molecules and MHC class II antigens highly, but their expression was not affected by IFN-gamma treatment. These changes in expression were accompanied by a decreased susceptibility to lysis by LAK cells. Treatment with antisense-intercellular-adhesion molecule-1 oligonucleotide further inhibited LAK lysis of target cells, following treatment with IFN-gamma. In contrast, acid treatment of tumor cells after treatment with IFN-gamma increased their susceptibility to lysis by LAK cells. These findings suggest that treatment of glioblastoma cells with IFN-gamma decreased their susceptibility to lysis by LAK cells, and that this decrease in susceptibility is attributable principally to the increased expression of MHC class I antigen on target cells.

The hypothesis was tested that hyperbaric oxygen therapy (HBO) reduced brain infarction by preventing apoptotic death in ischemic cortex in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and subsequently were exposed to HBO (2.5 atmospheres absolute) for 2 h, at 6 h after reperfusion. Rats were killed and brain samples were collected at 24, 48, 72 h, and 7 days after reperfusion. Neurologic deficits, infarction area, and apoptotic changes were evaluated by clinical scores, 2,3,7-triphenyltetrazolium chloride staining, caspase-3 expression, DNA fragmentation assay, and terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate-biotin nick end labeling (TUNEL)-hematoxylin and eosin (H&E) costaining. In MCAO/R without HBO treatment animals, DNA fragmentation was observed in injured cortex at 24, 48, and 72 h but not in samples at 7 days after reperfusion. Double labeling of brain slides with NeuN and caspase-3 demonstrated neurons in the injured cortex labeled with caspase-3. TUNEL+H&E costaining revealed morphologic apoptotic changes at 24, 48, and 72 h after reperfusion. Hyperbaric oxygen therapy abolished DNA fragmentation and reduced the number of TUNEL-positive cells. Hyperbaric oxygen therapy reduced infarct area and improved neurologic scores at 7 days after reperfusion. One of the molecular mechanisms of HBO-induced brain protection is to prevent apoptosis, and this effect of HBO might preserve more brain tissues and promote neurologic functional recovery.

Background The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases. Results In this study, we examined the function and regulation of calcium-activated potassium (KCa) channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a KCa channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a KCa channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found KCa channels and bradykinin type 2 receptors (B2R) expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain), human brain microvessel endothelial cells (HBMEC) and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of KCa channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of KCa channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of KCa channels, which may contribute to the overexpression of KCa channels in tumor microvessels and selectivity of BTB opening. Conclusion These findings suggest that KCa channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors.